1. Georg Nickenig, Universitatsklinikum Bonn, Germany Jan-Malte Sinning, Universitatsklinikum Bonn, Germany Jan Kovac, Glenfield Hospital, Leicester, UK Peter de Jaegere, Erasmus MC, Rotterdam, NL Anna-Sonia Petronio, Azienda Ospedaliero Universitaria Pisana, Italy (On Behalf of the ADVANCE II Investigators)

2. Accumulating clinical experience has led to the development of best-practice recommendations aimed at improving the results of the transcatheter aortic valve implantation (TAVI) procedure with the CoreValve system. These recommendations include:  Patient screening and valve size selection using multislice computed tomography  control of implant depth to 6 mm or less relative to the aortic annulus  adherence to international guidelines to determine the need for post-TAVI permanent pacemaker implantation Background CoreValve ADVANCE II Study 2

3. Study Design Purpose To implement best practices for CoreValve deployment and apply rigorous data collection and core laboratory analysis to assess outcomes Design Prospective, non-randomized, multicenter, observational study Follow-up at 7 days, 1 month, and 6 months Device CoreValve 23, 26, 29, and 31 mm Transfemoral, subclavian, and direct aortic routes Core Labs MSCT, angiography (implant depth), ECG, pacemaker interrogation, and echo Event Adjudication Adverse events according to VARC-2 by independent CEC Permanent pacemaker indications to 2007 ESC guidelines by independent adverse event advisory committee CoreValve ADVANCE II Study 3

4. HospitalPrincipal InvestigatorEnrollment Universitätsklinikum Bonn Bonn, DE Prof. Dr. med. G. Nickenig 40 Erasmus MC Rotterdam, NL Prof. P. de Jaegere 40 Azienda Ospedaliero Universitaria Pisana Pisa, IT Prof. ssa S. Petronio 35 Universitätsklinikum Heidelberg Heidelberg, DE Prof. Dr. med. R. Bekeredjian 22 University Hospital Antwerp Antwerp, BE Prof J. Bosmans 19 Istituto Clinico S. Ambrogio Milan, IT Prof. F. Bedogni 16 Cardiocenter Hospital Podlesi Třinec, CZ Dr. M. Branny 12 Charite, Campus Mitte – Kardiologie Berlin, DE Prof. Dr. med. K. Stangl 8 Glenfield Hospital Leicester, UK Dr. J. Kovac 8 CoreValve ADVANCE II Study 4 Participating Centers

5. Key Inclusion and Exclusion Criteria Inclusion Symptomatic aortic valve stenosis AVA 40 mmHg or jet velocity >4 m/s High risk for surgical AVR as determined by local heart teams Aortic annulus diameter 18-29 mm Exclusion Pre-existing device which regulated heart rhythm Pre-existing class I or II indication for permanent pacemaker Persistent and permanent atrial fibrillation Paroxysmal AF was not an exclusion criteria Purposeful patient selection to allow study of new conduction disturbances specifically due to TAVI CoreValve ADVANCE II Study 5

6. Medical history (N=200)% or mean ± SD Conduction (core lab, N=200)% or mean ± SD Age (yrs.) 80.2 ± 6.7 PQ interval (msec, mean ± SD )186.6 ± 39.3 Male 47.5 AV conduction Log EuroSCORE II 9.0 ± 8.9 Normal75.8 STS7.2 ± 6.8 1st degree AV block24.2 NYHA III / IV74.4 IV conduction CAD60.3 Normal76.8 PVD27.6 LBBB5.6 Cerebrovascular disease15.2 RBBB6.1 History of AF10.5 LAFB10.6 Prior MI 15.1 LPFB0.5 Prior PCI 30.8 Prior CABG 15.6 COPD 21.1 Permanent pacemaker**0.5 **One patient received a PPM after providing consent, but before the index procedure Baseline Characteristics CoreValve ADVANCE II Study 6

7. 1 Month6 Months (n) † Rate* (%)(n) † Rate* (%) All-cause mortality31.6 179.2 Cardiovascular mortality31.6 105.3 Stroke42.1 52.6 Major stroke21.0 31.6 Life-threatening or disabling bleeding84.1 105.4 Major bleeding2311.9 2412.4 Major vascular complications2311.9 2311.9 Myocardial infarction10.5 31.7 Acute kidney injury, stage III10.5 1 *Kaplan-Meier event rate † We only consider the first event in each complication category for a given patient Safety outcomes CoreValve ADVANCE II Study 7

8. †Kaplan-Meier rates Implant depth defined as the maximal distance between the intraventricular end of the bioprosthesis and the aortic annulus at the level of the non-coronary cusp, as measured by angiography in the projection chosen for deployment. Assessed by core laboratory. Primary Endpoint When CoreValve was deployed according to best practices, the resulting permanent pacemaker rate was 13.3% at 1 month CoreValve ADVANCE II Study 8

9. †Kaplan-Meier rates Implant depth defined as the maximal distance between the intraventricular end of the bioprosthesis and the aortic annulus at the level of the non-coronary cusp, as measured by angiography in the projection chosen for deployment. Assessed by core laboratory. Permanent Pacemaker Rate at 30 Days CoreValve ADVANCE II Study 9

10. †Kaplan-Meier rates Implant depth defined as the maximal distance between the intraventricular end of the bioprosthesis and the aortic annulus at the level of the non-coronary cusp, as measured by angiography in the projection chosen for deployment. Assessed by core laboratory. Permanent Pacemaker Rate at 6 Months CoreValve ADVANCE II Study 10

11. Intrinsic rhythm was determined by temporary VVI programming at 30 bpm 25 patients had data available at day 7 and 6 months for paired analysis Intrinsic Rhythm in Patients with Pacemakers CoreValve ADVANCE II Study 11 †McNemar’s test on paired data

12. Paired data showed that the amount of time ventricles were paced during the follow-up period decreased significantly from day 7 to 6 months (p=0.03 † ) Ventricular Pacing CoreValve ADVANCE II Study 12 †Signed Rank test comparing 7 day % ventricular pacing with 6 months for the 19 patients with paired data

13. New-onset Left Bundle Branch Block (LBBB) resolved with time Paired data showed 36.4% had resolved spontaneously by 6 months Patients with permanent pacemakers were excluded from this analysis Resolution of Left Bundle Branch Block CoreValve ADVANCE II Study 13 †McNemar’s test on paired data

14. Valve Performance CoreValve ADVANCE II Study 14

15. More than mild PVL decreased significantly over time (p=0.022 † ) Paravalvular Leak CoreValve ADVANCE II Study 15 †GEE logistic regression model for the odds of moderate/severe PVL over time using all available data at 7 days, 1 month, and 6 months

16. MR (≥ mild) decreased significantly over time (p=0.04 † ) Mitral Regurgitation CoreValve ADVANCE II Study 16 †GEE logistic regression model for the odds of more than mild MR over time using all available data at baseline, 7 days, 1 month, and 6 months

17. † Calculated from paired baseline and 6 month values, N=66 Wall Thickness CoreValve ADVANCE II Study 17

18. The proportion of subjects with LVEF ≥45% increased significantly over time (p=0.009 † ) Left Ventricular Ejection Fraction CoreValve ADVANCE II Study 18 †GEE logistic regression model for the odds of LVEF >45% over time using all available data at baseline, 7 days, 1 month, and 6 months

19. TCT 2013 LBCT NYHA Functional Status CoreValve ADVANCE II Study 19

20. Adherence to best clinical practices during CoreValve implant leads to the following 6-month outcomes: All-Cause Mortality = 9.2% All Stroke = 2.6% Pacemaker implantation rate = 14.5% for class I / II indications at ≤6 mm, 25.7% overall in patients with known implant depths (N=192/194) Spontaneous recovery from LBBB in 36.4% of patients Acute improvement in aortic valve hemodynamics with a trend of continued improvement with time Low post-procedural rate of moderate / severe PVL which decreased significantly to 4.3% Reverse cardiac remodeling Relief of heart failure symptoms Summary CoreValve ADVANCE II Study 20

21. Patient Disposition CoreValve ADVANCE II Study 21

22. Timing of Permanent Pacemaker Implantation CoreValve ADVANCE II Study 22 43 / 50 (86%) of pacemakers were implanted within the first month of TAVI

23. Valve Performance CoreValve ADVANCE II Study 23 †t-test from paired day 7 and 6 month values

24. Paired data show more than mild PVL decreased significantly from day 7 to 6 months (p=0.005 † ) Paravalvular Leak | Paired Analysis CoreValve ADVANCE II Study 24 †McNemar’s test on paired data

25. † Calculated from paired baseline and 6 month values, N=66 Left Ventricular Mass CoreValve ADVANCE II Study 25

26. Permanent Pacemaker Implant (PPI) status did not impact LVEF over time (p=0.74 † ) Left Ventricular Ejection Fraction CoreValve ADVANCE II Study 26 †GEE logistic regression model for the group effect, indicating if LVEF differs between pacemaker groups across time using all available data at baseline, 7 days, 1 month, and 6 months